Effects of Pioglitazone on Insulin and Glucose Metabolism in Women With Polycystic Ovary Syndrome (PCOS) (PCOS)

Determination if Indirectly Reducing Circulating Insulin by Improving Insulin Sensitivity With Pioglitazone Reduces Renal Clearance of D-chiro-inositol (DCI) Increases the Circulating Concentration of DCI and Enhances Insulin-stimulated Release of the D-chiro-inositol-containing Inositolphosphoglycan (DCI-IPG) Mediator in Obese Women With PCOS

Our hypothesis is that hyperinsulinemia increases the renal clearance of D-chiro-inositol (DCI) in women with polycystic ovary syndrome (PCOS) and that this leads to a reduction in circulating insulin-stimulated D-chiro-inositol-containing inositol phosphoglycan (DCI-IPG) release. To assess the effects of a chronic reduction in circulating insulin on DCI metabolism, we propose to reduce circulating insulin in obese women with PCOS by improving insulin sensitivity with the drug pioglitazone. Pioglitazone is a thiazolidinedione that improves peripheral insulin sensitivity, presumably by activation of the peroxisome proliferator-activated receptor gamma (PPARγ) receptor. Administration of pioglitazone to women with PCOS has been shown to improve insulin sensitivity, reduce insulin secretion, and decrease both fasting and post-prandial serum insulin concentrations.

Study Overview

• Status: Terminated
• Conditions: Polycystic Ovary Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: pioglitazone

Detailed Description

This protocol focuses on the hypothesis that a deficiency in a putative inositolphosphoglycan (IPG) mediator of insulin action, namely a D-chiro-inositol-containing IPG (DCI-IPG), contributes to the insulin resistance of some women with PCOS. Our interest in this area stems directly from our previous studies, which demonstrated that administration of the precursor, D-chiro-inositol (DCI), to both obese and lean women with PCOS improved glucose intolerance while reducing circulating insulin, and simultaneously improved ovulatory function and decreased serum androgens. These findings were recently confirmed in a large-scale study by an independent group. The findings of these three studies suggested that administration of DCI improved insulin sensitivity in PCOS, which then resulted in an improved hormonal and metabolic milieu.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University General Clinical Research Center
• Venezuela
  • Caracas, Venezuela, 1071
    • Hospital de Clinical Caracas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Obese (Body Mass Index or BMI greater than or equal to 30 kg/m2) women with PCOS between 18-40 years of age:

   • oligomenorrhea (less than 8 menstrual periods annually)
   • biochemical hyperandrogenemia (elevated total or free testosterone)
   • normal thyroid function tests and serum prolactin; AND
   • exclusion of 21a-hydroxylase deficiency by a fasting 17a-hydroxyprogesterone less than 200 ng/dl.51,
2. acceptable health on the basis of interview, medical history, physical examination, and laboratory tests (Complete Blood Chemistry or CBC, Comprehensive Metabolic Panel denoted SMA20, urinalysis, negative pregnancy test).
3. Signed, witnessed informed consent.
4. Ability to comply with study requirements.

Exclusion Criteria:

1. Diabetes mellitus by fasting glucose or oral glucose tolerance test (OGTT), or clinically significant pulmonary, cardiac, renal, hepatic, neurologic, psychiatric, infectious, neoplastic and malignant disease (other than non-melanoma skin cancer).
2. Current use of oral contraceptives.
3. Documented or suspected recent (within one year) history of drug abuse or alcoholism.
4. Ingestion of any investigational drug within two months prior to study onset.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Pioglitazone; Pioglitazone in pill form at 45mg twice per day for 6 months	Drug: pioglitazone; pioglitazone 45 mg
Placebo Comparator: 2/Placebo; Placebo control to arm 1 in pill form identical to treatment form also twice per day for 6 months	Drug: Placebo; placebo daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC DCI-IPG (%/Min)	Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT before treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.	Baseline
AUC DCI-IPG (%/Min)	Change in the Area Under the Curve DCI-IPG measurements in blood samples taken at 15 minute intervals during the 2 hour OGTT following 6 months of treatment with pioglitazone or placebo. Values reported as a percentage of bioactivity measured at time 0. Negative values indicate a decrease relative to the time 0 measurement.	6 months
Fasting Serum Insulin	Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT before treatment with either pioglitazone or placebo	baseline
Fasting Serum Insulin (uIU/ml)	Fasting serum insulin (uIU.min/ml) measured at 0, 60 and 120 minutes of a 2 hour OGTT following 6 months treatment with either pioglitazone or placebo	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Matsuda Index	Whole body insulin sensitivity as determined by the Matsuda Index as calculated using the following formula: 10,000 divided by the square root of (FPI* FPG) * (xGPC* xIPC) Where FPI is fasting plasma insulin expressed as uU/ml, FPG is fasting plasma glucose expressed as mg/dL, xGPC is mean plasma glucose concentration after the load and xIPC is the mean insulin concentration after the load. Values calculated on samples taken at 0, 30, 60, 90 and 120 minutes of a 2 hour OGTT. Values typically range from 0 to 12 units with higher scores indicating better insulin sensitivity. A value of 2.5 or less is indicative of insulin resistance.	Baseline
Matsuda Index	Whole body insulin sensitivity as determined by the Matsuda Index	6 months

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Investigators: Principal Investigator: John E. Nestler, M.D., Virginia Commonwealth University

Publications and helpful links

General Publications

• Gupta A, Jakubowicz D, Nestler JE. Pioglitazone Therapy Increases Insulin-Stimulated Release of d-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome. Metab Syndr Relat Disord. 2016 Oct;14(8):391-396. doi: 10.1089/met.2016.0009. Epub 2016 Mar 30.

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: March 22, 2009
• First Submitted That Met QC Criteria: March 23, 2009
• First Posted (Estimate): March 24, 2009

Study Record Updates

• Last Update Posted (Estimate): June 10, 2016
• Last Update Submitted That Met QC Criteria: May 2, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: VCUIRB4480; GCRC0824 (Other Identifier: Virginia Commonwealth University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: individual data kept confidential, secured and not shared beyond authorized study staff